Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive arthropathy. In spite of the prominence of the synovial inflammation, autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. Additional systemic immunological abnormalities include a defect that can best be summarized as accelerated immune aging. A putative role of age-dependent immune dysfunction in RA pathogenesis resonates with epidemiological data that RA is a disease of the second half of life with increasing incidence in the elderly. We have hypothesized that a defect in regulating T cell activation thresholds contributes to the tolerance failure and possibly also to the accelerated cellular aging. T cell activation thresholds are regulated by the signal strength originating from T-cell receptor (TCR) stimulation and by signals from costimulatory and coinhibitory cell surface receptors. We have found an increased responsiveness of the ERK pathway in RA T cells that is central to TCR calibration and amplifying signal strength and have proposed that mechanisms controlling the Raf-MEK-ERK module in T cells from RA patients have been reset to favor sustained signaling, thereby impairing peripheral immune tolerance. Our preliminary studies have identified several possible mechanisms causing this hyperresponsiveness including the increased transcription of B-RAF and K-RAS and the induction of a positive feedback loop induced by the homeostatic cytokines IL7 and IL15. The objective of the current application is to determine whether a characterization of these signaling abnormalities in individual RA patients is useful for patient classification and treatment design. Specific Aim 1 will explore the hypothesis that subsets of RA patients can be defined which differ in their mechanism to hyperstimulate the ERK pathway. Specific Aim 2 will determine whether the findings are limited to RA or also extend to other frequent arthritides such as psoriatic arthritis. In Specific Aim 3, we will determine whether existing standard (methotrexate, leflunomide or TNF inhibition) and newly emerging treatment approaches such as JAK3 inhibition are able to correct the signaling abnormalities In Specific Aim 4, we will examine the functional consequences of increased ERK responsiveness for T cell tolerance and T cell differentiation.